The compounds of the present invention have a novel structure characterised by the combination of an aminotriazole group, a hydrazide structure and an aromatic-type spacer. The compounds are used in the treatment of pathologies associated with the neuropeptide Y (NPY).
Various NPY receptor ligands have been described recently. By way of example, there may be mentioned cyclic peptide compounds (WO 9400486), amino acid compounds of arginine (WO 9417035) or non-peptide compounds (WO 9827063).
The Neuropeptide Y (NPY) is a peptide of 36 amino acids, related to the peptide YY (PYY) and to pancreatic polypeptides (PP). Originally isolated from pig brain (Proc. Natl. Acad. Sci., 1982, 79, 5485), NPY is widely distributed in mammals at the level of the central and peripheral nervous systems. This neurotransmitter is present in high concentrations in nerve fibres of the brain, but also of the heart, the sympathetic ganglia, blood vessels and smooth muscles of the vas deferens and of the gastrointestinal tract. It is responsible for various physiological effects which are exerted via the intermediary of specific receptors (Y). The latter form a heterogeneous group, 6 sub-types of which have been identified to date: Y1 to Y6 (Pharmacological Reviews, 1998, 50, 143). NPY is involved in eating behaviour by strongly stimulating food intake (Proc. Natl. Acad. Sci., 1985, 82, 3940), or by exerting a regulatory role on the HPA (hypothalamic-pituitary-adrenal) axis (J. of Neuroendocrinol., 1995, 7, 273). It also exhibits anxiolytic and sedative properties (Neuropsychopharmacology, 1993, 8, 357), a strong vasoconstrictive ability (Eur. J. Pharmacol., 1984, 85, 519) which induces an increase in blood pressure, and also has an effect on the circadian rhythm (Neuroscience and Biobehavioral Reviews, 1995, 19, 349).
In addition to the fact that the compounds of the invention are new, they have demonstrated an in vivo inhibitory action on food intake and weight gain. That effect is exerted via the intermediary of binding to the NPY receptors. It will thus be possible to use the compounds of the invention in the treatment of pathologies in which an NPY receptor ligand is necessary, especially in the treatment of pathologies associated with eating behaviour disorders or energy balance disorders, such as diabetes, obesity, bulimia, anorexia nervosa, and also in the treatment of arterial hypertension, anxiety, depression, epilepsy, sexual dysfunctions and sleep disorders.
The present invention relates especially to compounds of formula (I): 
wherein:
n is 0 or 1,
W represents a xe2x80x94COxe2x80x94 group or an S(O)q group wherein q is 0, 1 or 2,
the grouping 
represents a group selected from: 
Z represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group,
A represents a grouping selected from xe2x80x94A2xe2x80x94, xe2x80x94A1xe2x80x94A2xe2x80x94, xe2x80x94A2xe2x80x94A1xe2x80x94 and xe2x80x94A1xe2x80x94A2xe2x80x94A1xe2x80x94 wherein A1 is an alkylene group and A2 represents an optionally substituted phenylene, optionally substituted naphthylene, cycloalkylene, or optionally substituted heteroarylene group,
R represents a hydrogen atom, or an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group,
R1 represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group,
their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched group having from 1 to 6 carbon atoms,
the term xe2x80x9calkylenexe2x80x9d denotes a linear or branched bivalent radical containing from 1 to 6 carbon atoms,
the term alkenyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 double bond,
the term alkynyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 triple bond,
the term xe2x80x9carylxe2x80x9d denotes a phenyl, naphthyl, biphenyl, dihydronaphthyl or tetrahydronaphthyl group,
the term xe2x80x9cheteroarylxe2x80x9d denotes an unsaturated or partially unsaturated mono- or bi-cyclic group having from 5 to 11 ring members, containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur,
the terms xe2x80x9cphenylenexe2x80x9d and xe2x80x9cnaphthylenexe2x80x9d denote bivalent phenyl and naphthyl radicals, respectively,
the term cycloalkylene denotes a bivalent saturated cyclic radical having from 3 to 8 carbon atoms,
the term xe2x80x9cheteroarylenexe2x80x9d denotes a bivalent heteroaryl radical as defined hereinbefore,
the expression xe2x80x9coptionally substitutedxe2x80x9d applied to the terms xe2x80x9carylxe2x80x9d, xe2x80x9carylalkylxe2x80x9d, xe2x80x9cheteroarylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d means that those groups are substituted on their cyclic moiety by from 1 to 5 identical or different substituents selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, halogen, hydroxy, linear or branched perhalo-(C1-C6)alkyl, nitro, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), linear or branched (C1-C6)acyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (C1-C6)alkyl groups), linear or branched (C1-C6)acylamino, linear or branched (C1-C6)alkoxycarbonyl, formyl, carboxy, sulpho, nitrile, linear or branched (C1-C6)aminoalkyl (optionally substituted on the nitrogen atom by one or two linear or branched (C1-C6)alkyl group), linear or branched (C1-C6)thioalkyl (optionally substituted on the sulfur atom by a linear or branched (C1-C6)alkyl group), or linear or branched (C1-C6)hydroxyalkyl (optionally substituted on the oxygen atom by a linear or branched (C1-C6)alkyl group),
the expression xe2x80x9coptionally substitutedxe2x80x9d applied to the terms xe2x80x9cphenylenexe2x80x9d, xe2x80x9cnaphthylenexe2x80x9d or xe2x80x9cheteroarylenexe2x80x9d means that those groups are substituted by from one to three identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, halogen, hydroxy, linear or branched perhalo-(C1-C6)alkyl, nitro, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), linear or branched (C1-C6)acyl, formyl, carboxy, linear or branched (C1-C6)alkoxycarbonyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (C1-C6)alkyl groups), linear or branched (C1-C6)acylamino and nitrile.
Among the heteroaryl groups preference is given to the pyridyl, furyl, thienyl and indolyl groups.
Among the heteroarylene groups preference is given to the pyridinylene and pyrazinylene groups.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methane-sulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
An advantageous aspect of the invention relates to compounds of formula (I) wherein n is 1.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein n is 0.
Preferred compounds of the invention are those wherein W represents an SO2 group.
Preferred compounds of the invention are those wherein the grouping 
represents a group selected from: 
Other preferred compounds of the invention are those wherein the grouping 
represents a group selected from: 
In preferred compounds of formula (I), A represents a grouping A2, A2 being more especially a phenylene, pyridinylene or pyrazinylene group.
In other preferred compounds of formula (I), A represents a grouping xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A2xe2x80x94A1xe2x80x94, A2 being more especially a phenylene, pyridinylene or pyrazinylene group.
In the compounds of formula (I), R1 preferably represents an optionally substituted aryl group.
In the compounds of formula (I), R will advantageously be selected from hydrogen, and an optionally substituted aryl group (more especially phenyl), and an optionally substituted heteroaryl group (more especially pyridinyl, furyl or thienyl).
An advantageous aspect of the invention relates to compounds of formula (I) wherein Z represents a group selected from alkyl, optionally substituted aryl and optionally substituted heteroaryl group.
The present invention relates especially advantageously to compounds of formula (I) wherein n is 1, W represents an SO2 group, A represents a group selected from phenylene, pyridinylene and pyrazinylene, R1 represents an optionally substituted aryl group, R is selected from a hydrogen atom, an optionally substituted aryl group and an optionally substituted heteroaryl group, and Z represents an alkyl, an optionally substituted aryl group or an optionally substituted heteroaryl group.
The preferred aryl group of the invention is the phenyl group.
The invention relates most especially to the following compounds:
Nxe2x80x2-[4-({5-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}amino)benzoyl]-benzenesulphonohydrazide
4-methoxy-Nxe2x80x2-[4-({5-phenyl-1-[3-trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}-amino)benzoyl]benzenesulphonohydrazide
Nxe2x80x2-{4-[(5-phenyl-1H-1,2,4-triazol-3-yl)amino]benzoyl}benzenesulphonohydrazide
Nxe2x80x2-(4-{[5-phenyl-1-(2-pyridyl)-1H-1,2,4-triazol-3-yl]amino}benzoyl)benzenesulphonohydrazide
Nxe2x80x2-[4-({5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}amino)-benzoyl}benzenesulphonohydrazide
Nxe2x80x2-(4-{[5-oxo-1-(2-pyridyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}benzoyl)-benzenesulphonohydrazide
Nxe2x80x2-[(6-{[5-oxo-1-(2-pyridinyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl]amino}-3-pyridinyl)-carbonyl]benzenesulphonohydrazide.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein A is as defined for formula (I) and P represents a protecting group for the amine function,
which is reacted in the presence of a coupling agent with a compound of formula (III):
NH2xe2x80x94(NH)nxe2x80x94Wxe2x80x94Zxe2x80x83xe2x80x83(III)
wherein n, W and Z are as defined for formula (I),
to yield, after deprotection of the amine function by removal of the P group, a compound of formula (IV): 
wherein n, A, W and Z are as defined hereinbefore,
which compound (IV) is then condensed in a basic medium with an isothiocyanate of formula (V): 
xe2x80x83wherein Rxe2x80x21 is as defined for R1 in formula (I) or represents a linear or branched (C1-C6)alkoxy group,
to yield a compound of formula (VI): 
xe2x80x83wherein n, Rxe2x80x21, A, W and Z are as defined hereinbefore,
which compound of formula (VI) is:
either, when Rxe2x80x21 represents a linear or branched (C1-C6)alkoxy group, condensed in the presence of a coupling agent with a hydrazine of formula Rxe2x80x94NHxe2x80x94NH2, wherein R is as defined for formula (I), to yield a compound of formula (VII/a): 
xe2x80x83wherein R, A, n, W and Z are as defined hereinbefore, and Rxe2x80x21 represents a linear or branched (C1-C6)alkoxy group,
which compound (VII/a) cyclises, spontaneously or after treatment in an acid medium, depending upon the nature of the R group, to yield a mixture of the two compounds of formulae (I/a) and (I/b): 
xe2x80x83particular cases of the compounds of formula (I) wherein R, A, n, W and Z are as defined hereinbefore,
which compounds (I/a) and (I/b) may be separated according to conventional separation techniques,
or, when Rxe2x80x21 represents an R1 group as defined for formula (I), condensed in the presence of a coupling agent with a hydrazine of formula Rxe2x80x94NHxe2x80x94NH2, wherein R is as defined for formula (I), to yield a compound of formula (VII/b): 
xe2x80x83wherein R1, R, A, n, W and Z are as defined hereinbefore,
which compound (VII/b) is subjected to a cyclisation reaction followed by dehydration, spontaneously or after treatment in an acid medium, depending upon the nature of the R group, to yield a mixture of the two compounds of formulae (I/c) and (I/d): 
xe2x80x83particular cases of the compounds of formula (I) wherein R1, R, A, n, W and Z are as defined hereinbefore,
which compounds (I/c) and (I/d) may be separated according to conventional separation techniques,
which compounds (I/a), (I/b), (I/c) and (I/d) constitute the totality of the compounds of formula (I),
are separated, where appropriate, into their enantiomers and/or diastereoisomers according to a conventional separation technique,
are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), on its own or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal or transdermal administration, tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration, which may be oral, nasal, rectal or parenteral. The unit dose generally ranges from 0.05 to 500 mg for a treatment in from 1 to 3 administrations per 24 hours.
The following Examples illustrate the invention and do not limit it in any way. The structures of the compounds described were confirmed by the usual spectroscopic techniques.
The starting materials used are known products or are prepared according to known procedures.